Understanding pyrroline-5-carboxylate synthetase deficiency: clinical, molecular, functional, and expression studies, structure-based analysis, and novel therapy with arginine

作者：Martinelli Diego^*; Haeberle Johannes; Rubio Vicente; Giunta Cecilia; Hausser Ingrid; Carrozzo Rosalba; Gougeard Nadine; Marco Marin Clara; Goffredo Bianca M; Meschini Maria Chiara; Bevivino Elsa; Boenzi Sara; Colafati Giovanna Stefania; Brancati Francesco; Baumgartner Matthias R; Dionisi Vici Carlo

来源：Journal of Inherited Metabolic Disease, 2012, 35(5): 761-776.

DOI：10.1007/s10545-011-9411-8

Delta(1)-Pyrroline-5-carboxylate synthetase (P5CS) catalyzes the first two steps of ornithine/proline biosynthesis. P5CS deficiency has been reported in three families, with patients presenting with cutis/joint laxity, cataracts, and neurodevelopmental delay. Only one family exhibited metabolic changes consistent with P5CS deficiency (low proline/ornithine/citrulline/arginine; fasting hyperammonemia). Here we report a new P5CS-deficient patient presenting the complete clinical/metabolic phenotype and carrying p.G93R and p.T299I substitutions in the gamma-glutamyl kinase (gamma GK) component of P5CS. The effects of these substitutions are (1) tested in mutagenesis/functional studies with E.coli gamma GK, (2) rationalized by structural modelling, and (3) reflected in decreased P5CS protein in patient fibroblasts (shown by immunofluorescence). Using optical/electron microscopy on skin biopsy, we show collagen/elastin fiber alterations that may contribute to connective tissue laxity and are compatible with our angio-MRI finding of kinky brain vessels in the patient. MR spectroscopy revealed decreased brain creatine, which normalized after sustained arginine supplementation, with improvement of neurodevelopmental and metabolic parameters, suggesting a pathogenic role of brain creatine decrease and the value of arginine therapy. Morphological and functional studies of fibroblast mitochondria show that P5CS deficiency is not associated with the mitochondrial alterations observed in Delta(1)-pyrroline-5-carboxylate reductase deficiency (another proline biosynthesis defect presenting cutis laxa and neurological alterations).

• 出版日期2012-9